Alexion is paying a whopping $8.4 billion in cash and stock to acquire Synageva BioPharma, a biotech in Lexington, Massachusetts, whose sebelipase alfa enzyme replacement therapy for lysosomal acid lipase (LAL) deficiency is awaiting regulatory review in the US, Europe and Japan. The high price of the acquisition, announced in May, raises questions about whether Alexion, a rare disease specialist in Cheshire, Connecticut, sees broader application of the drug to treat fatty liver disease—specifically nonalcoholic steatohepatitis (NASH), which has been the focus of drug development by multiple companies (Nat. Biotechnol. 32, 705, 2014).

Infants with LAL deficiency accumulate cholesterol esters and triglycerides in the lysosomes of liver cells. Credit: Claudia Stocker/Science photo library

Sebelipase alfa (SBC-102), to be named Kanuma, is a recombinant version of the LAL enzyme. It is intended to break down cholesteryl esters and triglycerides that accumulate in individuals with inherited LAL deficiency. The disease, which affects between 8 and 12 people per million, leads to lipid accumulation in lysosomes in cells throughout the body, leading to severe complications, including fibrosis, cirrhosis, liver failure and dyslipidemia.

A complete lack of LAL in early childhood, called Wolman disease, is uniformly fatal without liver transplant. A milder form of LAL deficiency (in the 10–20% range of normal) usually manifests itself clinically in adolescence or adulthood as cholesteryl ester storage disease, and there is no standard treatment except for dietary changes. Some clinicians think that inherited forms of LAL deficiency are underdiagnosed, which would, if true, expand the market for LAL replacement therapy considerably. “The number of cases that are known are much less than you would anticipate from a population-based study looking for mutations in LAL,” says Joel Lavine 'professor of pediatrics/chief, gastroenterology, hepatology and nutrition' of Columbia University Medical Center.

It's also possible that a partial LAL deficiency exists in a subtype of patients with fatty liver disease. Nonalcoholic fatty liver disease is found in roughly 25–30% of adults, with about a seventh of those having NASH. “Maybe this [LAL deficiency] population is being lost in this bigger cohort,” Lavine says. As the fatty liver disease progresses, some patients become functionally deficient in LAL, exacerbating what would otherwise be a milder disease state. Then, enzyme replacement could potentially improve some disease parameters.

“We already know that NASH and NAFLD [nonalcoholic fatty liver disease] are very heterogeneous syndromes that will require multiple therapies,” says Rohit Loomba associate professor of clinical medicine of the University of California, San Diego. It may be useful to give LAL enzyme as a booster, to rid the liver of excessive lipid accumulation. “Then you see if it improves lysosomal function and ameliorates NASH,” he says. But given that patients with NASH have yet to even be assessed for the prevalence of functional or even mild deficiency, “I think this will take a long time,” he says. Synageva has conducted clinical trials in LAL deficiency in both children and adults. The company has not looked at whether the drug could improve NASH, nor has it looked at enzyme measures of NASH patients to see if there is any correlation with LAL deficiency.

How broadly sebelipase alfa might be used is uncertain. NASH and LAL deficiency diagnoses by liver biopsy are quite distinct, with not much overlap. In NASH, excess lipid accumulation in vesicles is sufficient to distort hepatocytes and move nuclei to the cellular periphery (macrovesicular hepatic steatosis), whereas in LAL deficiency the intracellular fat globules are markedly smaller (microvesicular hepatic steatosis). Also, biopsies of patients with LAL deficiency show the presence of foamy macrophages not found in NASH. According to Lavine, who is co-chair of the NASH Clinical Research Network Steering Committee of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the pathologists contributing expertise to the network are clear they have not mistaken a NASH patient for one deficient in the monogenic manifestations of LAL. Nor do individuals with NASH often exhibit the combination of very low HDL and high total cholesterol that is common in LAL deficiency.

“My gut feeling is [LAL enzyme replacement] will not be the panacea for NASH,” says Loomba. “It's farfetched and we have more promising therapies.” But Loomba also says that the development scheme for sebelipase alfa could provide valuable insights into how to use enzymes to solve other problems in fatty liver disease related to fat, protein or lipid accumulation inside the hepatocyte, including NASH.

In any case, Alexion will apply the usual thinking for developing the market for a rare disease. It will pound the pavement to identify patients, and emphasize disease education and new diagnostic initiatives—the strategy that brought it to prominence with Soliris (eculizumab), its antibody treatment for paroxysmal hemoglobinuria, an ultra-rare blood disorder in which chronic and uncontrolled activation of complement results in destruction of red blood cells. Alexion is also awaiting a US Food and Drug Administration decision on its asfotase alfa for hypophosphatasia, an ultra-rare, potentially fatal metabolic disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase.

In a call with investors, Alexion CEO David Hallal said that through the Synageva acquisition, and the anticipated approvals of asfotase alfa, the company is establishing “the foundation for the premier multi-billion dollar metabolic rare disease franchise.”

“I think the development of pharmaceutical agents to treat NASH is just beginning to blossom,” Loomba says. “We will see new products come in and the products that look promising today completely fade out. The field will look completely different in five years.”